Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gp IIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111. Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. See U.S. Pat. Nos. 4,578,079 and 4,614,517.
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. U.S. Pat. No. 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
Other synthetic peptides and their use as inhibitors of fibrinogen binding to platelets are disclosed by Koczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); Hayerstick et al., Blood 66 (4), 946-952 (1985); and Ruoslahti and Pierschbacher, Science 238, 497-497 (1987). Still other such inhibitory peptides are disclosed in EP Patent Applications 275,748 and 298,820.
U.S. Pat. No. 4,879,313 discloses compounds useful as inhibitors of platelet aggregation having the formula: ##STR2## wherein x=6 to 10,
y=0 to 4, PA1 Z=H, COOH, CONH.sub.2 OR C.sub.1-6 alkyl, PA1 Ar=phenyl, biphenyl or naphthyl, each substituted with 1 to 3 methoxy groups, or an unsubstituted phenyl, biphenyl, naphthyl, pyridyl or thienyl group, and PA1 Asp=aspartic acid residue. PA1 R.sub.2 represents a lower alkyl, lower alkenyl, lower alkynyl or benzyl group, or a lower alkoxycarbonylalkyl, lower carboxyalkyl, or lower hydroxyalkyl group; PA1 R.sub.3 and R.sub.4, identical or different, each represents a lower alkyl or lower hydroxyalkyl radical, lower alkenyl or lower alkynyl radical or form together with the nitrogen to which they are attached, a saturated heterocycle such as morpholino, thiomorpholino, pyrrolidino not substituted or substituted by an alkoxycarbonyl or carboxy group, piperazino, 4-(lower alkyl)piperazino, 4-(lower hydroxyalkyl)piperazino, or piperidino not substituted or substituted by one of the following groups: lower alkyl, benzyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl, hydroxyamino, alkoxycarbonyl or carboxy. PA1 Ar represents a phenyl, alpha-naphthyl or beta-naphthyl group, possibly substituted, or a heteroaryl group chosen from the radicals pyridyl, quinolinyl, or isoquinolinyl, possibly substituted, as well as their isomers and their mixtures and their salts with pharmaceutically acceptable mineral or organic acids PA1 R.sub.2 and R.sub.3, identical or different, each represents a lower alkyl or hydroxyalkyl, lower alkenyl or lower alkynyl radical, or they form together with the nitrogen to which they are attached, a saturated heterocycle such as morpholino, thiomorpholino, pyrrolidino unsubstituted or substituted by an alkoxycarbonyl or carboxyl group, piperazino, 4-(lower alkyl)-piperazino or piperidino unsubstituted or substituted by a lower alkyl, benzyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl, alkoxycarbonyl or carboxyl group. Ar represents a phenyl, a possibly substituted alpha-naphthyl or beta-naphthyl group, or else a heteroaryl group chosen from pyridyl, quinolinyl, isoquinolinyl, possibly substituted PA1 where PA1 Q.sup.1 stands for hydrogen, methyl or phenyl, PA1 Q.sup.2 stands for hydrogen, phenyl-low-alkyl or low alkyl that can be cleaved under physiological conditions, PA1 X stands for 1,4-phenylene, 2,5- or 3,6-pyridylene or, 1,4-piperidinylene, which is bonded to group Y through the C atom in the 4-position, PA1 Y is a group having the formula ##STR6## where Q.sup.3 stands for hydrogen, methyl, phenyl, --COOH, --COO--low-alkyl, --CONH(CH.sub.2).sub.2 --COOH or --CONH(CH.sub.2).sub.2 --COO-low-alkyl, PA1 Q.sup.4 hydrogen, methyl or phenyl, PA1 Z a 1,4-piperazinylene group, a 1,4-piperazinylene group which is bonded to the CO group through the N atom in the 1-position or a group having the formula EQU --NHCH(R.sup.1)-- or --NHCH(COR.sup.2)-- PA1 R.sup.1 stands for hydrogen, methyl, phenyl or a --COO-low-alkyl, PA1 R.sup.2 stands for the residue of an .alpha.-aminocarboxylic acid bonded through the amino group or of an ester or amide thereof, or a group having the formula --NHCH.sub.2 CH.sub.2 --Ar, or --CO--R.sup.2, or, if applicable, a mono- or di-low-alkylated carbamoyl group or a pyrrolidinoyl or piperidinoyl group, PA1 Ar stands for a phenyl or a phenyl substituted by low alkyl, low alkoxy, --COOH, --COO-low-alkyl, --O(CH.sub.2).sub.1-4 --COOH, --O(CH.sub.2).sub.1-4 --COO-low-alkyl, --CONH.sub.2, --CONH-low-alkyl, --CON(low alkyl).sub.2, pyrrolidinoyl or piperidinoyl which are said to have inhibitory action on the bonding of adhesive proteins to blood platelets as well as blood platelet aggregation and cell-cell adhesion. These compounds are structurally distinct from the present invention because they contain a second, mandatory carbonyl group. PA1 Y is alkylene having 1 to 6 carbon atoms, alkenylene having 2 to 4 carbon atoms, alkynylene having 2 to 4 carbon atoms or carboxamidoalkyl wherein the alkyl is 1 to 6 carbon atoms and PA1 Z is a group having the formula ##STR8## wherein R.sub.3 is alkyl having 1 to 6 carbon atoms; alkenyl having 2 to 4 carbon atoms; alkynyl having 2 to 4 carbon atoms; phenyl; substituted phenyl wherein each substituent can be selected from the group consisting of alkyl having 1 to 6 carbon atoms and alkoxy having 1 to 6 carbon atoms; phenylalkylamido wherein the alkyl is 1 to 6 carbon atoms and the alkyl chain may be interrupted by oxygen; substituted phenylalkylamido wherein the alkyl is 1 to 6 carbon atoms and the alkyl chain may be interrupted by oxygen and the phenyl substituents are selected from the group consisting of alkyl having 1 to 6 carbon atoms and alkoxy having 1 to 6 carbon atoms; hydroxy; amino; 5 or 6 carbon membered cyclic ring wherein one or two of the ring carbon atoms are replaced by a hetero atom which is selected from nitrogen, oxygen and sulfur with the proviso that when two hetero atoms are present one hetero atom must be nitrogen; alkylsulfonamido wherein the alkyl is 1 to 6 carbon atoms; phenylsulfonamido; or substituted phenylsulfonamido wherein each phenyl substituent can be selected from the group consisting of alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, and halo; and PA1 R.sub.4 is absent, hydrido or alkyl having 1 to 6 carbon atoms with the understanding that when R.sub.4 is absent, and R.sub.3 is absent or alkyl having 1 or 2 carbon atoms, the oxygen adjacent to R.sub.4 position can combine with R.sub.3 when present or can combine with the carbon adjacent to the carbonyl to form a lactone; PA1 Y is alkylene having 1 to 6 carbon atoms, alkenylene having 2 to 4 carbon atoms or alkynyl having 2 to 4 carbon atoms; PA1 Z is a group having the formula ##STR10## wherein R.sub.3 is phenylalkylamido wherein the alkyl is 1 to 6 carbon atoms and the alkyl chain may be interrupted by oxygen; substituted phenylalkylamido wherein the alkyl is 1 to 6 carbon atoms and the alkyl chain may be interrupted by oxygen and the phenyl substituents are selected from the group consisting of alkyl having 1 to 6 carbon atoms and alkoxy having 1 to 6 carbon atoms; and PA1 R.sub.4 is hydrido or alkyl having 1 to 6 carbon atoms. PA1 Y is alkylene having 1 to 6 carbon atoms, alkenylene having 2 to 4 carbon atoms or alkynylene having 2 to 4 carbon atoms; PA1 Z is a group having the formula ##STR12## wherein R.sub.3 is alkylsulfonamido wherein the alkyl is 1 to 6 carbon atoms; phenylsulfonamido, or substituted phenylsulfonamido wherein each phenyl substituent can be selected from the group consisting of alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms; and PA1 R.sub.4 is hydrido or alkyl having 1 to 6 carbon atoms.
This art is structurally distinct from the present invention because it lacks the phenylamidine moiety.
U.S. Pat. No. 4,977,168 discloses compounds having the following structural formula: ##STR3## wherein R.sub.1 represents hydrogen, a lower alkyl group, a lower hydroxyalkyl group, a benzyl group, a phenyl group or a 4-hydroxyphenyl group;
which are useful as antithrombotic agents. These compounds are structurally distinct from the present invention because they are arylsulphonylaminoacyl amino-phenylalaninamide derivatives in contrast to the compounds of the present invention which are propanoic acid esters-1-amidinophenyl alkylamino carbonyl derivatives.
U.S. Pat. No. 4,791,102 discloses compounds having the following structural formula ##STR4## wherein R.sub.1 represents a lower alkyl, lower hydroxyalkyl, or benzyl group, a phenyl or a 4-hydroxyphenyl group.
which are useful as selective inhibiting agents of thrombin and antithrombotics. These compounds are structurally distinct from the present invention because they are arylsulphonylaminoacyl aminophenylalaninamide derivatives in contrast to the compounds of the present invention which are propanoic acid esters-1-amidinophenyl alkylamino carbonyl derivatives.
European Patent Application 372,486 discloses N-acyl beta amino acid derivatives of the formula: ##STR5## and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis, and for inhibiting metastasis.
European Patent Application 381,033 A1 discloses amidino or guanidino-aryl substituted alkanoic acid derivatives which are useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and tumors. These compounds are structurally distinct from the present invention because they are aryl acetic acid/esters 2-amidino/guanidino substituted phenyl alkyl carbonyl amino derivatives in contrast to the compounds of the present invention which are propanoic acid/esters-1-amidinophenylalkyl aminocarbonyl derivatives.
European Patent Application 445,796 A2 discloses acetic acid derivatives having the formula EQU H.sub.2 N(NH)C--X--Y--CO--Z--CH(Q.sup.1)COOQ.sup.2
where
Goodman, et al., Accounts of Chemical Research 12, No. 1, 1-7 (January 1979) discloses a stereochemical analysis of retro-isomers of cyclic and linear peptides.